Biopraxis proposes to develop its mu SERS platform technology as a high-throughput mix-and-measure screening (HTS) assay for antiviral drug lead identification and optimization. Unlike current HTS assays, mu SERS does not rely on labels. Instead, surface-enhanced Raman fingerprints are collected directly from the biomolecule. These fingerprints contain a rich body of information on the chemistries of the biomolecule and any ligands bound to it. Therefore, unlike other technologies which simply determine whether binding takes place, mu SERS can also tell which ligands were bound, and even produce information on how they were bound (i.e., on the binding chemistries involved). HIV-1 reverse transcdptase (RT) will be used as a model system on Phase I to demonstrate the unique capabilities of the technology. On Phase II, mu SERS will be developed into a flexible tool that can be used to screen small molecule libraries against diverse HIV targets (e.g., integrase, trans-activation-responsive RNA, or envelope glycoproteins). The tool will comprise a mu SERS chip reader; a miniature 'nanowell plate' chip and associated microfluidics for handling tiny samples; and software for analysis of small ligands binding any type of biomolecule. The analyses will be exceptionally sensitive, consuming trace amounts of biomolecules and chemical libraries; very rapid, requiring only a single incubation to allow binding to take place, plus a few seconds to collect and process the spectra; and flexible, able to accommodate studies on, e.g., binding interactions with biomolecule complexes, competitive, synergistic, or antagonistic binding, and/or the impact of pH or metal ions on ligand binding interactions.